This is a continuing analysis of the development of neuronal circuitry in cerebral neocortex. A quantitative electron microscopic method is used to analyze the radial distribution of synapses in somatosensory cortex of newborn rat. Pilot studies are projected for perinatal primate neocortex. The aim is to determine in what layers of cortex early-formed synapses are located. In newborn rat, synapses are sparse; they are confined to layers that are parallel to the surface. We will continue to study this stratiform pattern of synaptogenesis at later stages of development, e.g., 14, 21 and 28 days postnatal. These data will provide parameters of normal synapse development and are needed as a base for more detailed analyses of circuitry formation in cortex. The morphologic characteristics of synapses are being analyzed in immature neocortex to determine if there are fine structural differences between synapses in different strata. Preliminary results suggest that there are such differences in respect to synapse size and identity of the post-synaptic element. These structural differences may reflect differences in origin and/or function of synapses at different cortical depths, in newborn as in adult. Histochemical methods are being used to identify cortical synapses by their transmitter, their pharmacologic properties and the locations of the cell-bodies-of-origin. Initial results employing an EM histochemical method revealed that a large percentage of synapses in newborn cortex are monoaminergic (MA) and presumably arise from the brainstem. The majority of these synapses are in layer IV, where the major thalamo-cortical input also terminates. One aim of this study is to identify the natural transmitter used by these MA terminals by means of both EM and fluorescence histochemistry. Cells of origin will be studied by lesion techniques, also persistence to adult.